In January of this year, Cambridge, UK based specialist ion channel CRO and drug discovery company Metrion Biosciences Limited, and LifeArc, a leading UK medical research charity, entered into a collaboration agreement for an ion channel drug discovery project in the field of neuroscience. The project aims to identify novel selective small-molecule modulators of a specific ion channel target that human patient gene association studies have identified as likely to be involved in neurological pathogenesis.
Metrion Biosciences supports early-stage drug discovery programmes including small-molecule, antibody and peptide-based approaches; all of which it can support with its assay technologies. The company’s clients include biotech companies, mid-size and large pharma, virtual companies, charities and academic institutions to which it provides high-quality screening and selectivity profiling assays, these assays generally being configured to meet the needs of each individual therapeutic target.
“Metrion Biosciences was a relatively new company when I joined in October 2016, founded with a very clear objective to provide ion channel drug discovery services of the highest quality to the life science industry,” comments company COO Dr Andrew Southan. “As an ion channel specialist with more than 30 years’ experience gained in academia, pharma and in a CRO environment, I saw significant potential for a UK-based ion channel specialist CRO to create a highly successful international business.
“We have been working with LifeArc since early 2017 and have established an excellent collaborative relationship with their team,” he continues. “The recently executed drug discovery agreement with LifeArc is for a very exciting drug discovery target in an area of ion channel science where LifeArc’s scientists have made some excellent progress to date. It also gives us clear visibility on a proportion of our revenue over a defined period, one of the great advantages of collaborative FTE-based contracts. Metrion’s Head of Drug Discovery, Dr Edward Stevens, who was appointed only last year, played a pivotal role in securing the LifeArc collaboration and brings extensive pharma industry experience to Metrion. His knowledge, alongside that of our CSO, Marc Rogers, and other members of the Metrion senior team means we are able to take a highly proactive role in discussions with potential new clients, contributing ideas and extensive drug discovery know-how during discussion of new therapeutic targets and programmes.”
Dr Andrew Southan, COO of Metrion Biosciences: "significant potential for a UK-based ion channel specialist CRO to create a highly successful international business"
LifeArc is a medical research charity that brings together a network of partners to tackle specific diseases and directly funds academic and early-stage research and will have responsibility for all new chemical syntheses in the collaborative research project, while Metrion will conduct the ion channel screening necessary to support drug discovery. In addition, Metrion will provide support for LifeArc’s medicinal chemistry target optimisation via its extensive suite of drug discovery assays, including high-quality automated and conventional electrophysiology, translational neuroscience, and cardiac safety profiling assays. The project commenced in January and will run for an initial period of twelve months, with an option to extend for a further twelve months based upon achievement of mutually agreed criteria. If successful, LifeArc will be responsible for further development of the programme.
Metrion also has an extensive range of Comprehensive In Vitro Proarrhythmia Assay (CiPA) compliant cardiac safety assays: CiPA is an FDA initiative to create new in-vitro and in-silico assay standards for cardiac safety evaluation of new drugs to provide a more accurate and comprehensive mechanistic-based assessment of proarrhythmic potential of drug candidates.
“We also have substantial experience of induced pluripotent stem cell (iPSC) assays and have generated extensive validation data packs for iPSC cardiomyocytes using cells created by vendors such as Ncardia, which was formerly Axiogenesis and Pluriomics, Cellular Dynamics International and Axol Biosciences,” adds Southan.
Metrion’s research facilities are based at Granta Park near Cambridge, UK, one of the largest bioscience hubs in Europe, and alongside companies such as MedImmune, AstraZeneca, Pfizer, Vernalis and Alzheimer’s Research UK. “We have sufficient room for the foreseeable future to expand the company in our current laboratories,” says Southan.
Metrion currently has 23 staff including its directors and support staff. Southan points out that for its scientific staff, the company places very strong emphasis on conventional electrophysiology expertise, together with an understanding of ion channel biophysics and pharmacology, as their core skill set: “The team also has significant depth of experience in automated electrophysiology and impedance/ microelectrode array assay platforms and includes pioneers of the development and use of automated electrophysiology technology in drug discovery research. All client-facing senior Metrion staff are PhD qualified, with the remainder being qualified to MSc or BSc level or having many years of laboratory experience.”
Metrion has two ongoing FTE-based collaborations and, according to Southan, is making very good progress to add additional FTE-based contracts throughout the course of 2019 to replace recently concluded collaborative contracts: “We are, however, not totally reliant on such collaborations, as our business model blends collaborative FTE-based long-term work with shorter-term fee-for-service contracts and grant-funded research and development,” he says. “A significant proportion of our revenue is generated from repeat fee-for-service customers, especially in important international markets such as the US and Japan. In addition, and for cardiac safety services in particular, we are seeing significant numbers of clients signing advance purchase orders to use Metrion throughout 2019, giving us good visibility on our pipeline.”
Southan says that ion channels provide significant opportunities as targets for drug discovery, having a broad distribution throughout the body and a wide breadth of families, subtypes and functionalities: “In addition to the well-known and proven therapies such as antihypertensive, antiepileptic and pain medication, there remain vast, untapped therapeutic potential and significant opportunities to improve the side effect profile of existing approved drugs acting via ion channel modulation,” he says. “Historically, ion channels have been a difficult target class for the pharmaceutical industry as their multiple conformations and conductance states complicate drug-binding properties and many screening technologies are not suited to such a complex and dynamic class of proteins. I believe, however, that developments in screening technology, increasing knowledge of the structural biology of ion channels, and improved computational chemistry techniques provide great opportunity to move forward successfully with innovative drug design and discovery ion channel projects.
“The significance and importance of ion channel function to normal human physiology and pathology should not be underestimated,” he continues. “The flow of ions across cell membranes, exquisitely controlled by precise, genetically determined individual ion channels, is the essence of living organisms. Without ion channels our hearts would not function, we would not be able to walk, talk, think or see. Ion channels are also involved in the secretion of certain hormones, and our understanding of this area is still evolving. Ion channel dysfunction is therefore more pivotally involved in disease states than was generally recognised in the past: the advent of genomics has identified multiple ion channel-disease associations and Metrion is well placed to capitalise on such developments, either via our own extensive target class knowledge or through collaboration with strategic partners.”
Southan observes that fluorescence-based assay technologies have been in existence for some time and can be applied to ion channel research: “They certainly have a place in the screening cascade and we work with our partner Assay.Works to provide access to such assays as hit-finding tools. However, although fluorescence techniques have been refined over the years, they lack the exquisite control of the assay that is enabled by electrophysiology techniques, therefore Metrion focuses its expertise in this area,” he says, adding that the use of human iPSC-derived differentiated tissue cells in drug discovery is now an increasingly important translational step in the drug discovery cascade: “The ion channel functionalities of individual cell types can not only be utilised to characterise and validate the differentiated status of the cells themselves, but can be used as a functional readout of the response of such cells to individual medicines and novel drugs. The development of human stem cell translational assays in drug discovery is a field in which we are already involved and that we believe is likely to expand rapidly.
“I also believe that advances in structural biology will provide us with significant opportunities for ion channel drug discovery research, especially now that cryo‐EM appears to be superseding crystallography as the technique of choice for determining near‐atomic resolution structures of ion channels. By understanding the conformational changes in ion channel structure at the atomic level and combining increasingly powerful computational chemistry tools for drug design, we will be able to more fully understand the opportunities to intervene in ion channel function and thereby facilitate the design of novel therapeutic molecules.”
Metrion Senior Scientist Dr Edward Humphries preparing samples for analysis
Southan says that at this time Metrion has an encouraging pipeline for 2019 and that the company expects the geographic range of its collaborative agreements to further expand this year: “Historically, we have worked with UK, mainland EU and Japanese collaborators, however, our US-based business advisor, Dr Chris Mathes,who has more than 25 years of experience in the ion channel field and who contributed to the early development and marketing strategy of automated patch clamp systems, has helped us to make significant progress in the US over the past twelve months and we are currently progressing discussions for high-value contracts with a number of clients in this territory. We have also engaged a specialist Japanese business development agency and Japan is now a significant territory for our business which we aim to further expand in 2019 and beyond.”
Biosciences outsourcing: "here to stay"
Southan says it is difficult to make a definitive judgement about what may happen in the future for the drug discovery sector, but that he does believe that outsourcing is here to stay within all sectors of the biosciences industry: “Significant expertise has been lost within the internal infrastructure of many pharmaceutical companies and this gap is now being filled with specialist CROs. I expect there to be increasing opportunities for specialist CROs to fill these capability gaps and Metrion is very well placed to capitalise on this,” he concludes, and provides the following example:
“Alongside its CRO activities, in January of last year, Metrion gained the rights to a large portfolio of small-molecule potassium channel inhibitors from Japan Tobacco Inc and during 2018 identified highly potent and selective orally-active small-molecule inhibitors of the Kv1.3 ion channel, which is fundamentally involved in the mechanisms of auto-immune diseases. Metrion is developing the potential of these assets further with the help of funding from Innovate UK and we see significant potential in the compounds for a variety of clinical indications, including auto-immune disorders such as rheumatoid arthritis, psoriasis and type-1 diabetes and, in the longer term, in multiple sclerosis and neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. Metrion aims to partner these assets in 2019 and has an active programme of meetings with companies interested in the therapeutic potential of these compounds.”
Metrion Scientist Sam Manyweathers sets up the Patchliner automated patch clamp platform...
...and Senior Scientist Dr Richard Davies operates it
For further information about Metrion Biosciences visit www.metrionbiosciences.com
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